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Herein we report the design and construction of chimeric oligonucleotides comprising a 2\u2032\u2010OMe\u2010modified antisense oligonucleotide and a 5\u2032\u2010phosphorylated 2\u2032\u20105\u2032 poly(A)\n                    <jats:sub>4<\/jats:sub>\n                    (4A\n                    <jats:sub>2\u20105<\/jats:sub>\n                    ) to degrade envelope and spike RNAs of SARS\u2010CoV\u20102. The oligonucleotide was used for searching and recognizing target viral RNA sequence, and the conjugated 4A\n                    <jats:sub>2\u20105<\/jats:sub>\n                    was used for guided RNase L activation to sequence\u2010specifically degrade viral RNAs. Since RNase L can potently cleave single\u2010stranded RNA during innate antiviral response, degradation efficiencies with these chimeras were twice as much as those with only antisense oligonucleotides for both SARS\u2010CoV\u20102 RNA targets. In pseudovirus infection models, chimera\u2010S4 achieved potent and broad\u2010spectrum inhibition of SARS\u2010CoV\u20102 and its N501Y and\/or \u0394\n                    <jats:italic>H<\/jats:italic>\n                    69\/\u0394\n                    <jats:italic>V<\/jats:italic>\n                    70 mutants, indicating a promising antiviral agent based on the nucleic acid\u2010hydrolysis targeting chimera (NATAC) strategy.\n                  <\/jats:p>","DOI":"10.1002\/anie.202105942","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T03:38:03Z","timestamp":1626665883000},"page":"21662-21667","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Efficient Inhibition of SARS\u2010CoV\u20102 Using Chimeric Antisense Oligonucleotides through RNase L 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